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The years 1999 and 2000 marked important milestones in the development of Glivec^® (imatinib).

Phase 1 Study: Unprecedented Responses With No Maximum Tolerated Dose

Preliminary results from the phase 1 dose-escalation study were reported first at the American Society of Clinical Oncology (ASCO) annual meeting and then updated at the American Society of Hematology (ASH) annual meeting in 1999. The study, conducted in patients with chronic-phase CML resistant/refractory to or intolerant of interferon-alfa (IFN-α), had started patient accrual a year earlier, in June 1998.

Even in early data presented by Dr Brian J. Druker at the ASCO annual meeting, there was evidence of the rates of response that would later make headlines¹⁸. By December 1999, 31 patients who received 4 weeks of therapy with Glivec at a dose of 300 mg/d or higher achieved complete haematological responses. Final results from this phase 1 dose-escalation study conducted in 83 patients with chronic-phase chronic myeloid leukaemia (CML) resistant/refractory to or intolerant of IFN-α confirmed that Glivec was generally well tolerated. There was a trend toward more frequent grade 3 and 4 events at doses of 750 mg/d. However, no maximum tolerated dose was identified up to 1000 mg/d¹⁹.

All of these late chronic-phase CML patients given doses of 140 mg/d achieved a haematological response, with complete responses observed in 98% of patients at doses ≥300 mg/d, with a median follow-up of 265 days. Major cytogenetic responses developed in 31% of patients at doses ≥300 mg/d; 13% of these cytogenetic responses were complete (no evidence of Philadelphia [Ph] chromosome)¹⁹. The levels of response and time to response achieved in this study were unprecedented in CML.

Pilot Study: Substantial Activity in Blast-Crisis Disease

At the ASCO 2000 annual meeting, Moshe Talpaz, MD, presented results for 33 patients in a pilot study of Glivec in blast-crisis CML or Ph chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL). All but 7 patients had previously received chemotherapy. Patients were treated with Glivec doses ranging from 300 to 600 mg daily. This small study focused on the group of patients with the most severe disease and the worst prognosis: the most challenging test yet for Glivec. At the time of the report, an impressive 55% of myeloid-blast-crisis patients have achieved responses²⁰.

The final results from the dose-escalation pilot study, which enrolled a total of 58 patients with blast-crisis CML or Ph+ ALL, confirmed that 55% of myeloid-blast-crisis patients achieved haematological responses and 11% achieved complete haematological responses²¹. Importantly, 7 of the 21 patients with myeloid blast crisis who had a response continued receiving Glivec and remained in remission from 101 days to 349 days after starting therapy. Glivec was well tolerated by these patients as well.

In 1999, 3 international, multicentre, single-group phase 2 studies testing Glivec in 3 separate populations of patients with CML were begun. Efficacy and safety data from these pivotal studies were the basis of the Glivec approval for CML treatment by health authorities worldwide.

Late Chronic Phase

The first study was conducted in patients with late-chronic-phase disease who were resistant to, refractory to, or intolerant of IFN-α²². The study enrolled 532 patients, 454 of whom had a confirmed diagnosis of chronic-phase (CP) CML. Glivec administration was initiated at a dose of 400 mg/d and could be escalated to 800 mg/d in patients who failed to achieve predefined milestones. The key efficacy end point was major cytogenetic response, and secondary end points included complete haematological response, time to progression, and overall survival²².

At 37-month follow-up in this study (Study 110), 65% of the patients achieved a major cytogenetic response that was complete in 53% (confirmed 43%) of patients. A complete haematological response was achieved in 95% of patients³. Five-year follow-up results have demonstrated 67% confirmed major cytogenetic responses in patients²³.Six-year follow-up results indicate that Glivec substantially improves the survival in patients with CP CML who previously failed IFN therapy. This report also confirms the beneficial effects of cytogenetic responses on long-term outcomes with Glivec24.

Accelerated Phase

The second study enrolled 235 patients, 181 of whom had a confirmed diagnosis of accelerated-phase CML²⁵. Glivec administration was started at a dose of 400 mg/d, but was increased to 600 mg/d once phase 1 dose-escalation data demonstrated the safety of prolonged treatment with higher doses. Dose escalation up to 400 mg twice daily was permitted when haematological response was not achieved after 1 month of therapy. The primary end point was sustained haematological response lasting at least 4 weeks. Secondary end points included duration of haematological response, cytogenetic response, time to progression, and overall survival (OS).

At 40.5-month follow-up in this study (Study 109), a confirmed haematological response was achieved in 71.5% of patients. Importantly, 27.7% of patients also achieved a major cytogenetic response, which was complete in 20.4% (confirmed 16%) of patients³. For the patients treated at 600 mg daily, the estimates for median progression-free-survival (PFS) and OS were 22.9 and 42.5 months, respectively.

Blast Crisis

The third study enrolled 260 patients, 229 of whom had a confirmed diagnosis of CML in myeloid blast crisis²⁶. As for accelerated-phase patients, Glivec was initially given at a dose of 400 mg/d and later was increased to 600 mg/d. The primary efficacy end point was sustained haematological response lasting at least 4 weeks, and secondary end points included duration of haematological response, cytogenetic response, and overall survival.

At 38-month follow-up in this study (Study 102), 31% of patients achieved a haematological response (36% in previously untreated patients and 22% previously treated patients). The rate of response was also higher in the patients treated at 600 mg/d (33%) as compared with the patients treated at 400 mg/d (16%, P = 0.0220). The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively³.

Safety

Glivec continues to be generally well tolerated and has demonstrated excellent efficacy and durable responses in patients with CML. The most frequently reported drug-related adverse events were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps, and rash—which were easily manageable; superficial oedemas were also a common finding³ . Fewer than 5% of patients have experienced serious adverse effects (such as skin rashes, liver toxicity, fluid retention syndrome, and haemorrhages) that led to discontinuation of treatment. The mechanism of the oedema remains to be elucidated, but it might be related to the more serious phenomenon of "fluid retention" that was reported in 1%-2% of patients and includes pleural effusion, ascites, pulmonary oedema, and rapid weight gain. Cytopaenia was a consistent finding in all studies, but tended to be more frequent in advanced-phase disease and at doses >750 mg daily. Two deaths were suspected to be related to Glivec administration in the advanced-phase population. One was attributed to acute liver failure in conjunction with paracetamol use, and the other was related to fluid retention and renal insufficiency³ . Cardiac disorders including cardiac tamponade and skin disorders including acute febrile neutrophilic dermatosis (Sweet's syndrome) have rarely (≤1/1000) been reported³ .

The effectiveness of Glivec is based on overall haematological and cytogenetic response rates and PFS in CML. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival³.

On May 10, 2001, only 3 years after the initiation of the phase 1 study in CML, Glivec was approved by the FDA US Food and Drug Administration (FDA)²⁷ for the treatment of this disease in patients who failed to benefit from IFN-α therapy. The regulatory review of Glivec set the record-14 weeks- for the fastest approval of any cancer drug in history. As a condition of the fast-track approval, Novartis agreed to continue clinical study of Glivec to gain a better understanding of the long-term effects of the drug²⁸. Soon after its introduction to the market in the United States, Glivec received approvals in the European Union and Japan.

In June 2000, the first patients were enrolled in the International Randomised Study of Interferon and STI571 (IRIS). This ambitious phase 3 trial (also known as Study 106) was unique in both size and scope. The IRIS investigators recruited 1106 patients at 177 centres in 16 countries to conduct a head-to-head comparison between Glivec and what was then the standard of care for patients with CML not undergoing bone marrow transplantation (BMT) as their initial therapy. Patients with newly diagnosed CML in chronic phase were randomly assigned in equal numbers to receive either Glivec 400 mg/d or a combination of IFN-α plus low-dose cytarabine (Ara-C). Dose escalations were permitted in both treatment arms if predetermined response criteria milestones were not met. Notably, crossover from one treatment arm to the other was allowed in the event of failure to respond or tolerate the initially assigned treatment²⁹.

The superior efficacy of Glivec over the regimen of IFN-α + Ara-C was apparent even at the earliest stages of the trial, the first report of which was presented in 2002 at ASCO by Dr Druker³⁰. Later that year at the ASH annual meeting, Dr Richard A. Larson, MD, of the University of Chicago, Illinois, USA, reported 14-month IRIS results of complete haematological, major cytogenetic, and complete cytogenetic response rates of 94%, 83%, and 68%, respectively, for the Glivec group and 55%, 20%, and 7%, respectively, for the IFN-α group (P = 0.001)³¹. Glivec was better tolerated than the combination regimen, with adverse events in the Glivec group mostly mild to moderate in severity²⁹.

Shortly after the ASH meeting, on December 19, 2002, health authorities in Europe approved Glivec for first-line treatment of CML in chronic phase. The FDA approved the new indication on December 20. Approvals in other countries followed rapidly.

CHR, complete haematological response; MCyR, major cytogenetic response; CCyR, complete cytogenetic response; PFS, progression-free survival; OS, overall survival.
*Data on file. Novartis Pharmaceuticals.

The availability of long-term follow-up data now indicates that Glivec provides a substantial survival benefit. Five-year follow-up data available from the IRIS trial demonstrates an estimated 98% of patients in chronic-phase CML have had their blood counts stabilised, and 92% of patients have had a major cytogenetic response with Glivec. Estimated 5-year survival rates of 89% have been reported for patients with newly diagnosed chronic-phase CML receiving 400 mg of Glivec^{1, 2}. And although more frequent adverse reactions, including gastrointestinal haemorrhages, conjunctivitis, and elevation of transaminases or bilirubin, were seen in the 800 mg/d group, other adverse reactions were reported with lower or equal frequency³.

Glivec Preclinical and Clinical Development in GIST

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